Phenotypic and Functional Characterisation of Human B-cell Response in Pemphigus

NCT04117529 | Unknown

• 2 other identifiers: APHP1901992019-A00533-54
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

Pemphigus is a rare autoimmune disease involving skin and mucous membranes characterized by the production of pathogenic autoantibodies directed against desmosomal transmembrane glycoproteins belonging to the cadherin family,responsible for the disruption of desmosomes leading to the acantholysis phenomenon.Two main classical subtypes of pemphigus have been individualized:pemphigus vulgaris and foliaceus,in which pathogenic autoantibodies are directed against desmoglein 3 and 1 respectively.The knowledge about B-cell populations responsible for pemphigus activity increased a lot.In pemphigus patients,B-cell population was shown to comprise auto-reactive B lymphocytes producing antibodies targeting desmogleins,directly responsible for disease activity,and regulatory B lymphocytes.After rituximab treatment,clinical activity was proved to be associated with circulating auto-antibodies high titers and an increase of auto-reactive B-cells,whereas clinical remission was associated with a change in B-cell populations,as B cell repertoire changed from oligoclonal to polyclonal when reconstituting after treatment,with an increase of immatures and transitional B-cells producing IL-10.The mechanisms leading to autoreactive B-cells appearance,the precise role of B-reg in immune tolerance and the factors triggering the imbalance between pro autoimmune and regulatory immune B-cells leading to pemphigus activity remain to be discovered.Polymorphonuclear neutrophil granulocytes(PMN) are the first responders of the immune system to threats by invading microorganisms.Since 2004, PMN were shown to produce neutrophil extracellular traps(NET),structures consisting of decondensed chromatin embedded with histones,granular and cytoplasmic proteins that trap and kill microbes.In lupus recent works demonstrated evidences that NETs components are found in immune complexes responsible for tissue inflammation and that polyclonal activation of B-cell as well as memory B-cell activation could be obtain in presence of immune complexes derived from NET.Besides lupus,other works showed evidence of NETs implication in inflammatory and auto-immune states in rheumatoid arthritis and small vessel vasculitis.The hypotheses is that B-cell activation by NET might not be restricted to autoimmune diseases of which antibodies target NETs components.The aim is to assess the effects on B-cell activation and the phenotypic changes in B-cell population from pemphigus patients after stimulation by NET.

Conditions

Pemphigus Vulgaris; Pemphigus Foliaceus

Keywords

Pemphigus Vulgaris; Pemphigus Foliaceus; B-cell; Dermatology

Outcome Measures

Primary Outcomes (1)

• Involvement of neutrophil extracellular traps (NETs) in the activation of B lymphocytes in Pemphigus

  This primary outcome measure is composite. It will be verified according to the following points : Measurement of activation parameters of total, auto-reactive, and regulator B lymphocytes of patients : * Quantification of membrane markers for activation of B lymphocytes (CD80, CD86, CD40) * Quantification of the production of pro-inflammatory cytokines (IL-6, IL-8, Tumor Necrosis Factor alpha (TNF alpha), IFNγ) by total and auto-reactive B lymphocytes * Quantification of the total production of immunoglobulins and antibodies specific for the disease * Quantification of IL-10 and Tumor Growth Factor (TGF) beta production by regulatory B cells.

  9 months after inclusion

Secondary Outcomes (4)

• Demonstration that activation of the different sub-populations of B lymphocytes during NET exposure, if shown in pemphigus, is also in lupus, rheumatoid arthritis and Gougerot-Sjögren's syndrome relying on membrane markers for activation of B lymphocytes

  9 months after inclusion

• Demonstration that activation of the different sub-populations of B lymphocytes during NET exposure, if shown in pemphigus, is also lupus, rheumatoid arthritis and Gougerot-Sjögren's syndrome relying on pro-inflammatory cytokines

  9 months after inclusion

• Demonstration that activation of the different sub-populations of B lymphocytes during NET exposure, if shown in pemphigus, is also in lupus, rheumatoid arthritis and Gougerot-Sjögren's syndrome relying on immunoglobulins and antibodies

  9 months after inclusion

• Demonstration that activation of the different sub-populations of B lymphocytes during NET exposure, if shown in pemphigus,is also in lupus,rheumatoid arthritis and Gougerot-Sjögren's syndrome relying on IL-10 and TGFbeta production by regulatory B cells

  9 months after inclusion

Study Arms (1)

Experimental Arm

EXPERIMENTAL

Pemphigus or other autoimmune diseases.

Other: Blood sample

Interventions

Blood sample OTHER

Collection of 2 blood sample : The first one at the inclusion in the study, the second one between 6 months and 9 months after the inclusion. The sample consists of 2 tubes of EthyleneDiamineTetraAcetic (EDTA) of 7 mL.

Experimental Arm

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients man or woman
• Patients above 18 years old
• Patients fulfilling the diagnostic criteria for pemphigus (Lever et al, 1979), or for lupus (SLICC 2012), or for rheumatoid arthritis (ACR / EULAR 2009 criteria), or for Gougerot-Sjögren's syndrome (ACR criteria / EULAR 2016)
• Clinically active disease, defined by the presence of erosions or cutaneo-mucous bubbles for pemphigus, a SLEDAI score\> 0 for lupus, a DAS28\> 0 score for rheumatoid arthritis, and an EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score\> 0 for Gougerot-Sjögren's syndrome
• Patients consenting to participate in the study
• Patients benefiting from the national healthcare insurance

You may not qualify if:

• Pregnant or lactating woman
• Patient already treated with biotherapy
• Patient already receiving treatment that may affect lymphocyte B populations: corticosteroid therapy\> 10 mg / d or other immunosuppressant.
• Patient whose weight and / or hemoglobin level does not allow an additional blood sample during the assessment already provided by the treatment (according to the values in Appendix 2 of the Decree of April 12, 2018, which lists the research mentioned in 2 ° of Article L. 1121-1 of the Public Health Code)
• Person deprived of liberty by judicial or administrative decision, person subject to a legal protection measure

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• Institut National de la Santé Et de la Recherche Médicale, France: collaborator

Study Sites (1)

Pr Philippe MUSETTE - Hôpital AVICENNE

Bobigny, 93000, France

RECRUITING

Related Publications (5)

• Langan SM, Smeeth L, Hubbard R, Fleming KM, Smith CJ, West J. Bullous pemphigoid and pemphigus vulgaris--incidence and mortality in the UK: population based cohort study. BMJ. 2008 Jul 9;337(7662):a180. doi: 10.1136/bmj.a180.

  PMID: 18614511 BACKGROUND

• Hashimoto T, Amagai M, Garrod DR, Nishikawa T. Immunofluorescence and immunoblot studies on the reactivity of pemphigus vulgaris and pemphigus foliaceus sera with desmoglein 3 and desmoglein 1. Epithelial Cell Biol. 1995;4(2):63-9.

  PMID: 8688919 BACKGROUND

• Martel P, Joly P. Pemphigus: autoimmune diseases of keratinocyte's adhesion molecules. Clin Dermatol. 2001 Nov-Dec;19(6):662-74. doi: 10.1016/s0738-081x(00)00191-7. No abstract available.

  PMID: 11705674 BACKGROUND

• Amagai M, Tsunoda K, Zillikens D, Nagai T, Nishikawa T. The clinical phenotype of pemphigus is defined by the anti-desmoglein autoantibody profile. J Am Acad Dermatol. 1999 Feb;40(2 Pt 1):167-70. doi: 10.1016/s0190-9622(99)70183-0.

  PMID: 10025740 BACKGROUND

• Mahoney MG, Wang Z, Rothenberger K, Koch PJ, Amagai M, Stanley JR. Explanations for the clinical and microscopic localization of lesions in pemphigus foliaceus and vulgaris. J Clin Invest. 1999 Feb;103(4):461-8. doi: 10.1172/JCI5252.

  PMID: 10021453 BACKGROUND

MeSH Terms

Conditions

Pemphigus

Interventions

Blood Specimen Collection

Condition Hierarchy (Ancestors)

Skin Diseases, Vesiculobullous; Skin Diseases; Skin and Connective Tissue Diseases; Autoimmune Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques

Study Officials

• Philippe MUSETTE, Pr

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Mohammed RAHAOUI, Mr

CONTACT

+33148955977; mohammed.rahaoui@aphp.fr

Gérôme BOHELAY, Dr

CONTACT

+33148955189; gerome.bohelay@gmail.com

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 26, 2019
• First Posted: October 7, 2019
• Study Start: October 22, 2019
• Primary Completion: July 1, 2022
• Study Completion: July 1, 2022
• Last Updated: January 8, 2021

Record last verified: 2020-12

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)